This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study entitled "Omega-3 Fatty Acids for Treatment of Major Depression" is an NIH funded grant, sponsored by the National Institute for Mental Health (NIMH) and the National Center for Complementary &Alternative Medicine (NCCAM). The total project period is from 12/01/2005 through 11/30/2010 and is in collaboration with Massachusetts General Hospital. As major depression is a common mental disorder, it has a profound negative impact on people[unreadable]s lives. Despite the availability of numerous therapies, the current treatment of depression is not optimal. Recently, evidence has surfaced suggesting that the dietary intake of polyunsaturated fatty acids (PUFAs), such as omega-3 fatty acid, might be related to depression and cardiovascular disease. The intake of omega-3 fatty acids in the western diet has decreased dramatically relative to omega-6 intake over the past century. Coincident with this change in diet, the incidence of major depressive disorder has markedly increased in western societies. It has been suggested that this modern western urban lifestyle characterized by high stress, little rest, and high intake of processed (i.e. omega-6-rich) foods creates a [unreadable]pro-inflammatory[unreadable] state that may contribute to the development of mood disorders in some individuals. As been demonstrated in cardiology research studies, omega-3 supplements may correct this omega-6:omega-3 ratio imbalance, and reverse this pro-inflammatory state. Recent studies also suggest that omega-3 dietary supplementation at about 5 times the standard dietary intake may yield clinically significant antidepressant effects;however little is known about the mechanisms of this effect. There is also little existing information comparing and contrasting the efficacy of the two major omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). This study will focus primarily the antidepressant efficacy of therapy with EPA vs. DHA vs. placebo in the treatment of major depression. We will also investigate the relationship between lipid metabolism and measures of immune function. The entire study at both study sites will randomize a total of 300 patients diagnosed with major depressive disorder over the entire 5 years of this study. Following a one-week washout period for subjects on antidepressants, subjects will be randomly assigned to double-blind treatment with either 1 gram/day EPA, DHA, or placebo. Subjects will undergo follow-up visits on a bi-weekly basis thereafter (weeks 2, 4, 6, and week 8 endpoint). All visits will include psychiatric assessment testing. Blood sampling will be performed at the first and last visits for analysis of lipid profiles, cardiovascular, and immunological assessments.